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Abstract

The collective actions of epithelial cells drive tissue shape changes, whether these are tightly organized during development or disorganized as during cancer invasion. In both cases, the motility of the bulk tissue is determined by the signaling and mechanical properties of its constituent cells. Decades of careful study have coalesced into detailed models that describe how individual cells move through their environment. Motility relies on the dynamics of lamentous actin, which cells use to maintain their shape and adhere to their surroundings during migration. Precisely connecting single cell properties with tissue behaviors to which they contribute would furnish critical advances to the understanding of of cancer invasion and tissue development. This thesis describes the application of model epithelial tissues toward bridging these scales, focusing on the formin family of actin lament nucleators. We employ Madin Darby Canine Kidney (MDCK) cells, as a model for tissue shape changes to study its requirements in a controlled 3D environment. Both MDCK cells and mouse tumor explants require the activity of formin proteins to undertake tissue migration into prepared collagen gels. We analyzed separately cell motility within the 2D plane of the epithelium from invasive motility into the collagen gel. These modes of cell motility are distinguished by the depletion of the formin protein Dia1. We show that invasive motility requires Dia1, which regulates cell adhesions to individual collagen brils. Finally, we capitalize on a simple mathematical model describing cell shape for epithelial monolayers. Applying this model to MDCK acini reveals that under quiescent conditions Dia1 enforces an immobile\"jammed" state within epithelia. This immobile state is released upon growth factor stimulation or loss of Dia1. Overall this work forges novel connections between cytoskeletal regulators at the single- and multi-cell scales, and prompts new hypotheses to test how cell behaviors contribute to tissue functions in health and disease.

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